Pulmonary Delivery for Levodopa

ABSTRACT

In one aspect, the invention is related to a method of treating a patient with Parkinson&#39;s disease, the method including administering to the respiratory tract of the patient particles that include more than about 90 weight percent (wt %) of levodopa. The particles are delivered to the patient&#39;s pulmonary system, preferably to the alveoli or the deep lung.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/055,959, filed Octt. 17, 2013 which is a continuation of U.S.application Ser. No. 13/773,054, filed Feb. 21, 2013, now U.S. Pat.8,586,093, issued Nov. 19, 2013, which is a continuation of U.S.application Ser. No. 12/972,824, filed Dec. 20, 2010 now U.S. Pat.8,404,276, issued Mar. 26, 2013, which is a divisional of U.S.application Ser. No. 10/392,342, filed Mar. 19, 2003, now U.S. Patent7,879,358, issued Feb. 1, 2011, (now RE43,711, issued Oct. 2, 2012),which claims the benefit of U.S. Provisional Application No. 60/366,471,filed Mar. 20, 2002. The entire teachings of the above applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Parkinson's disease is characterized neuropathologically by degenerationof dopamine neurons in the basal ganglia and neurologically bydebilitating tremors, slowness of movement and balance problems. It isestimated that over one million people suffer from Parkinson's disease.Nearly all patients receive the dopamine precursor levodopa or L-Dopa,often in conjunction with the dopa-decarboxylase inhibitor, carbidopa.L-Dopa adequately controls symptoms of Parkinson's disease in the earlystages of the disease. However, it tends to become less effective aftera period which can vary from several months to several years in thecourse of the disease.

It is believed that the varying effects of L-Dopa in Parkinson's diseasepatients are related, at least in part, to the plasma half life ofL-Dopa which tends to be very short, in the range of 1 to 3 hours, evenwhen co-administered with carbidopa. In the early stages of the disease,this factor is mitigated by the dopamine storage capacity of thetargeted striatal neurons. L-Dopa is taken up and stored by the neuronsand is released over time. However, as the disease progresses,dopaminergic neurons degenerate, resulting in decreased dopamine storagecapacity. Accordingly, the positive effects of L-Dopa becomeincreasingly related to fluctuations of plasma levels of L-Dopa. Inaddition, patients tend to develop problems involving gastric emptyingand poor intestinal uptake of L-Dopa. Patients exhibit increasinglymarked swings in Parkinson's disease symptoms, ranging from a return toclassic Parkinson's disease symptoms, when plasma levels fall, to theso-called dyskinesis, when plasma levels temporarily rise too highfollowing L-Dopa administration.

As the disease progresses, conventional L-Dopa therapy involvesincreasingly frequent, but lower dosing schedules. Many patients, forexample, receive L-Dopa every two to three hours. It is found, however,that even frequent doses of L-Dopa are inadequate in controllingParkinson's disease symptoms. In addition, they inconvenience thepatient and often result in non-compliance.

It is also found that even with as many as six to ten L-Dopa doses aday, plasma L-Dopa levels can still fall dangerously low, and thepatient can experience very severe Parkinson's disease symptoms. Whenthis happens, additional L-Dopa is administered as intervention therapyto rapidly increase brain dopamine activity. However, orallyadministered therapy is associated with an onset period of about 30 to45 minutes during which the patient suffers unnecessarily. In addition,the combined effects of the intervention therapy, with the regularlyscheduled dose can lead to overdosing, which can requirehospitalization. For example, subcutaneously administered dopaminereceptor agonist (apomorphine), often requiring a peripherally actingdopamine antagonist, for example, domperidone, to controldopamine-induced nausea, is inconvenient and invasive.

Therefore, a need exists for methods of treating patients suffering withParkinson's disease which are at least as effective as conventionaltherapies yet minimize or eliminate the above-mentioned problems.

SUMMARY OF THE INVENTION

The invention relates to methods of treating disorders of the centralnervous system (CNS). More specifically the invention relates toparticles and methods for delivering a drug suitable in treatingParkinson's disease, e.g., levodopa, to the pulmonary system.

In one aspect, the invention is related to a method of treating apatient with Parkinson's disease, the method including administering tothe respiratory tract of the patient particles that include more thanabout 90 weight percent (wt %) of levodopa. The particles are deliveredto the patient's pulmonary system, preferably to the alveoli region ofthe deep lung.

In one embodiment of the invention, the particles also include anon-reducing sugar, e.g., trehalose and, optionally, a salt, e.g.,sodium chloride (NaCl).

In another embodiment of the invention, the particles also include aphospholipid, e.g., DPPC, or a combination of phospholipids, andoptionally a salt, e.g., NaCl.

The invention is also related to a method of preparing spray driedparticles that have a high content of L-Dopa, e.g., more than about 90wt %. The method includes combining L-Dopa, trehalose, NaCl and water toform an aqueous solution and preparing an organic solution (e.g.,ethanol), mixing the aqueous solution and organic solution to form aliquid feed mixture and spray drying the liquid feed mixture, therebyforming spray dried particles.

The invention further is related to methods for administering to thepulmonary system a therapeutic dose of L-Dopa in a small number ofsteps, and preferably in a single, breath activated step. The inventionalso is related to methods of delivering a therapeutic dose of L-Dopa tothe pulmonary system, in a small number of breaths, and preferably in asingle breath.

The invention has numerous advantages. The particles of the inventionare useful in treating all stages of Parkinson's disease, e.g., ongoingmanagement of the disease, as well as providing rescue therapy. Theparticles have a high content of L-Dopa and, therefore, the amount ofdrug that can be contained and administered from a given inhaler capsuleis increased, thereby reducing the number of puffs required to deliver aclinically effective dose. The methods of the invention result informing dry, non-sticky particles in high yields, minimizing materiallosses and manufacturing costs. The particles have aerodynamic anddispersive properties that render them useful in pulmonary delivery, inparticular delivery to the deep lung.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the invention, either as steps of theinvention or as combination of parts of the invention, will now be moreparticularly described and pointed out in the claims. It will beunderstood that the particular embodiments of the invention are shown byway of illustration and not as limitations of the invention. Theprinciple feature of this invention may be employed in variousembodiments without departing from the scope of the invention.

The invention is generally related to methods of treating Parkinson'sdisease. The methods and particles disclosed herein can be used in theongoing (non-rescue) treatment of Parkinson's disease or during the latestages of the disease, when the methods described herein areparticularly well suited to provide rescue therapy. As used herein,“rescue therapy” means on demand, rapid delivery of a drug to a patientto help reduce or control disease symptoms.

Compounds used for treating Parkinson's disease include levodopa(L-Dopa) and carbidopa. The structure of Carbidopa is shown below:

The structure of Levodopa is shown below:

Other drugs generally administered in the treatment of Parkinson'sdisease and which may be suitable in the methods of the inventioninclude, for example, ethosuximide, dopamine agonists such as, but notlimited to carbidopa, apomorphine, sopinirole, pramipexole, pergoline,bronaocriptine, and ropinirole. The L-Dopa or other dopamine precursoror agonist may be any form or derivative that is biologically active inthe patient being treated. Combinations of drugs also can be employed.

In one embodiment of the invention the particles consist include L-Dopaor other dopamine precursor or agonist as described above. Particularlypreferred are particles that include more than about 90 weight percent(wt %), for instance, at least 93 wt % L-Dopa. In one embodiment, theparticles include at least 95 wt % L-Dopa. In other embodiments, thepresence of a non-reducing sugar or the presence of a salt, as will bedescribed herein, facilitates a lower L-Dopa wt % while maintainingfavorable features. The wt % of L-Dopa can be lower to about 75 wt %, orto about 50 wt %, or to about 20 wt %.

In further embodiments, the particles of the invention can also includeone or more additional component(s), generally in an amount that is lessthan 10 weight percent.

In one embodiment the additional component is a non-reducing sugar, forexample, but not limited to, trehalose, sucrose, fructose. Trehalose ispreferred. Combinations of non-reducing sugars also can be employed. Theamount of non-reducing sugar(s), e.g., trehalose, present in theparticles of the invention generally is less than 10 wt %, for example,but not limited to, less than 8 wt %, or less than 6 wt %.

Without wishing to be held to a particular interpretation of theinvention, it is believed that non-reducing sugars enhance the stabilityof a drug, such as L-Dopa, that has chemical groups, e.g., amine group,that can potentially react with a sugar that is reducing, e.g., lactose.It is further believed the presence of non-reducing sugars rather thanreducing sugars also can benefit compositions that include otherbioactive agents or drugs, such as, for example, Carbidopa, epinephrineand other catecholamines.

In another embodiment, the particles of the invention include, inaddition to L-Dopa, one or more phospholipids. Specific examples ofphospholipids include but are not limited to phosphatidylcholinesdipalmitoyl phosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), distearoyl phosphatidylcholine (DSPC),dipalmitoyl phosphatidyl glycerol (DPPG) or any combination thereof. Theamount of phospholipids, e.g., DPPC, present in the particles of theinvention generally is less than 10 wt %.

The phospholipids or combinations thereof and methods of preparingparticles having desired release properties are described in U.S.application Ser. No. 09/792,869 entitled “Modulation of Release from DryPowder Formulations”, filed on Feb. 23, 2001 under Attorney Docket No.2685.1012-004, which is a continuation-in-part of U.S. application Ser.No. 09/644,736 entitled “Modulation of Release from Dry PowderFormulations”, filed on Aug. 23, 2000 under Attorney Docket No.2685.1012-001, both of which claim the benefit of U.S. ProvisionalPatent Application No. 60/150,742 entitled “Modulation of Release FromDry Powder Formulations by Controlling Matrix Transition”, filed on Aug.25, 1999. The contents of all three applications are incorporated hereinby reference in their entirety.

Optionally, the particles include, in addition to a non-reducingsugar(s) or phospholipid(s), a small amount of a strong electrolytesalt, such as, but not limited to, sodium chloride (NaCl). Other saltsthat can be employed include sodium phosphate, sodium fluoride, sodiumsulfate and calcium carbonate. Generally, the amount of salt present inthe particles is less than 10 wt %, for example, less than 5 wt %.

Particles that comprise, by weight, greater than 90% of an agent, e.g.,L-Dopa, can have local areas of charges on the surface of the particles.This electrostatic charge on the surface of the particles causes theparticles to behave in undesirable ways. For example, the presence ofthe electrostatic charge will cause the particles to stick to the wallsof the spray drying chamber, or to the pipe leading from the spraydryer, or to stick within the baghouse, thereby, significantly reducingthe percent yield obtained. Additionally, the electrostatic charge cantend to cause the particles to agglomerate when placed in a capsulebased system. Dispersing these agglomerates can be difficult and thatcan manifest itself by either poor emitted doses, poor fine particlefractions, or both. Moreover, particle packing can also be affected bythe presence of an electrostatic charge. Particles with like charges inclose proximity will repel each other, leaving void spaces in the powderbed. This results in a given mass of particles with an electrostaticcharge taking up more space than a given mass of the same powder withoutan electrostatic charge. Consequently, this limits the upper dose thatcan be delivered in a single receptacle.

Without wishing to be held to a particular interpretation of theinvention, it is believed that a salt, such as NaCl, provides a sourceof mobile counter-ions. It is believed that the addition of a small saltto particles that have local areas of charge on their surface willreduce the amount of static present in the final powder by providing asource of mobile counter-ions that would associate with the chargedregions on the surface. Thereby the yield of the powder produced isimproved by reducing powder agglomeration, improving the Fine ParticleFraction (FPF) and emitted dose of the particles and allowing for alarger mass of particles to be packed into a single receptacle. As seenin Table 1, particles comprising L-Dopa and either trehalose or DPPC,with the addition of sodium chloride, show an increased yield ofapproximately 50-60 fold.

TABLE 1 Formulation Ratio Yield L-Dopa/Trehalose 95/5 <1%L-Dopa/Trehalose/NaCl 93/5/2 50% L-Dopa/DPPC 95/5 <1% L-Dopa/DPPC/NaCl90/8/2 62%

Table 2 depicts the effects of sodium chloride on the fine particlefraction and emitted dose of particles comprising L-Dopa and eithertrehalose or DPPC.

TABLE 2 Formulation Ratio FPF < 5.6 FPF < 3.4 L-Dopa/Trehalose 95/5 3312 L-Dopa/Trehalose/NaCl 93/5/2 59 40 L-Dopa/DPPC 95/5 29 10L-Dopa/DPPC/NaCl 90/8/2 70 54

It is believed that the salt effect described above also benefitscompositions that include bioactive agents other than L-Dopa. Examplesof such active agents include, but are not limited to, Carbidopa,epinephrine, other catecholamines, albuterol, salmeterol, ropinirole andpiroxican. Furthermore, compositions that include 90% or less of abioactive agent, e.g., L-Dopa, also can benefit from adding a salt suchas described above.

The particles of the invention can include a surfactant. As used herein,the term “surfactant” refers to any agent which preferentially absorbsto an interface between two immiscible phases, such as the interfacebetween water and an organic polymer solution, a water/air interface ororganic solvent/air interface. Surfactants generally possess ahydrophilic moiety and a lipophilic moiety, such that, upon absorbing tomicroparticles, they tend to present moieties to the externalenvironment that do not attract similarly-coated particles, thusreducing particle agglomeration. Surfactants may also promote absorptionof a therapeutic or diagnostic agent and increase bioavailability of theagent.

Suitable surfactants which can be employed in fabricating the particlesof the invention include but are not limited to Tween-20; Tween-80;hexadecanol; fatty alcohols such as polyethylene glycol (PEG);polyoxyethylene-9-lauryl ether; a surface active fatty acid such aspalmitic acid or oleic acid; glycocholate; surfactin; a poloxamer; asorbitan fatty acid ester such as sorbitan trioleate (Span 85); andtyloxapol.

Other materials which promote fast release kinetics of the medicamentcan also be employed. For example, biocompatible, and preferablybiodegradable polymers can be employed. Particles including suchpolymeric materials are described in U.S. Pat. No. 5,874,064, issued onFeb. 23, 1999 to Edwards et al., the teachings of which are incorporatedherein by reference in their entirety.

The particles can also include a material such as, for example, dextran,polysaccharides, lactose, cyclodextrins, proteins, peptides,polypeptides, amino acids, fatty acids, inorganic compounds, phosphates.

Particles of the invention are suitable for delivering L-Dopa to thepulmonary system. Particles administered to the respiratory tract travelthrough the upper airways (oropharynx and larynx), the lower airwayswhich include the trachea followed by bifurcations into the bronchi andbronchioli and through the terminal bronchioli which in turn divide intorespiratory bronchioli leading then to the ultimate respiratory zone,the alveoli or the deep lung. The particles can be engineered such thatmost of the mass of particles deposits in the deep lung or alveoli.

The particles of the invention can be administered as part of apharmaceutical formulation or in combination with other therapies bethey oral, pulmonary, by injection or other mode of administration. Asdescribed herein, particularly useful pulmonary formulations are spraydried particles having physical characteristics which favor target lungdeposition and are formulated to optimize release and bioavailabilityprofiles.

The particles of the invention can be employed in compositions suitablefor drug delivery to the pulmonary system. For example, suchcompositions can include the particles and a pharmaceutically acceptablecarrier for administration to a patient, preferably for administrationvia inhalation.

The particles of the invention are useful for delivery of L-Dopa to thepulmonary system, in particular to the deep lung. The particles are inthe form of a dry powder and are characterized by a fine particlefraction (FPF), geometric and aerodynamic dimensions and by otherproperties, as further described below.

Gravimetric analysis, using Cascade impactors, is a method of measuringthe size distribution of airborne particles. The Andersen CascadeImpactor (ACI) is an eight-stage impactor that can separate aerosolsinto nine distinct fractions based on aerodynamic size. The size cutoffsof each stage are dependent upon the flow rate at which the ACI isoperated. Preferably the ACI is calibrated at 60 L/min.

In one embodiment, a two-stage collapsed ACI is used for particleoptimization. The two-stage collapsed ACI consists of stages 0, 2 and Fof the eight-stage ACI and allows for the collection of two separatepowder fractions. At each stage an aerosol stream passes through thenozzles and impinges upon the surface. Particles in the aerosol streamwith a large enough inertia will impact upon the plate. Smallerparticles that do not have enough inertia to impact on the plate willremain in the aerosol stream and be carried to the next stage.

The ACI is calibrated so that the fraction of powder that is collectedon a first stage is referred to as fine particle fraction FPF (5.6).This FPF corresponds to the % of particles that have an aerodynamicdiameter of less than 5.6 μm. The fraction of powder that passed thefirst stage of the ACI and is deposited on the collection filter isreferred to as FPF(3.4). This corresponds to the % of particles havingan aerodynamic diameter of less than 3.4 μm.

The FPF (5.6) fraction has been demonstrated to correlate to thefraction of the powder that is deposited in the lungs of the patient,while the FPF(3.4) has been demonstrated to correlate to the fraction ofthe powder that reaches the deep lung of a patient.

The FPF of at least 50% of the particles of the invention is less thanabout 5.6 μm. For example, but not limited to, the FPF of at least 60%,or 70%, or 80%, or 90% of the particles is less than about 5.6 μm.

Another method for measuring the size distribution of airborne particlesis the multi-stage liquid impinger (MSLI). The Multi-stage liquidImpinger (MSLI) operates on the same principles as the Anderson CascadeImpactor (ACI), but instead of eight stages there are five in the MSLI.Additionally, instead of each stage consisting of a solid plate, eachMSLI stage consists of an methanol-wetted glass frit. The wetted stageis used to prevent bouncing and re-entrainment, which can occur usingthe ACI. The MSLI is used to provide an indication of the flow ratedependence of the powder. This can be accomplished by operating the MSLIat 30, 60, and 90 L/min and measuring the fraction of the powdercollected on stage 1 and the collection filter. If the fractions on eachstage remain relatively constant across the different flow rates thenthe powder is considered to be approaching flow rate independence.

The particles of the invention have a tap density of less than about 0.4g/cm³. Particles which have a tap density of less than about 0.4 g/cm³are referred to herein as “aerodynamically light particles”. Forexample, the particles have a tap density less than about 0.3 g/cm³, ora tap density less than about 0.2 g/cm³, a tap density less than about0.1 g/cm³. Tap density can be measured by using instruments known tothose skilled in the art such as the Dual Platform MicroprocessorControlled Tap Density Tester (Vankel, NC) or a GEOPYCTM instrument(Micrometrics Instrument Corp., Norcross, Ga. 30093). Tap density is astandard measure of the envelope mass density. Tap density can bedetermined using the method of USP Bulk Density and Tapped Density,United States Pharmacopia convention, Rockville, Md, 10^(th) Supplement,4950-4951, 1999. Features which can contribute to low tap densityinclude irregular surface texture and porous structure.

The envelope mass density of an isotropic particle is defined as themass of the particle divided by the minimum sphere envelope volumewithin which it can be enclosed. In one embodiment of the invention, theparticles have an envelope mass density of less than about 0.4 g/cm³.

The particles of the invention have a preferred size, e.g., a volumemedian geometric diameter (VMGD) of at least about 1 micron (μm). In oneembodiment, the VMGD is from about 1 μm to 30 μm, or any subrangeencompassed by about 1 μm to 30 μm, for example, but not limited to,from about 5 μm to about 30 μm, or from about 10 μm to 30 μm. Forexample, the particles have a VMGD ranging from about 1 μm to 10 μm, orfrom about 3 μm to 7 μm, or from about 5 μm to 15 μm or from about 9 μmto about 30 μm. The particles have a median diameter, mass mediandiameter (MMD), a mass median envelope diameter (MMED) or a mass mediangeometric diameter (MMGD) of at least 1 μm, for example, 5 μm or near toor greater than about 10 μm. For example, the particles have a MMGDgreater than about 1 μm and ranging to about 30 μm, or any subrangeencompassed by about 1 μm to 30 μm, for example, but not limited to,from about 5 μm to 30 μm or from about 10 μm to about 30 μm.

The diameter of the spray-dried particles, for example, the VMGD, can bemeasured using a laser diffraction instrument (for example Helos,manufactured by Sympatec, Princeton, N.J.). Other instruments formeasuring particle diameter are well know in the art. The diameter ofparticles in a sample will range depending upon factors such as particlecomposition and methods of synthesis. The distribution of size ofparticles in a sample can be selected to permit optimal deposition totargeted sites within the respiratory tract.

Aerodynamically light particles preferably have “mass median aerodynamicdiameter” (MMAD), also referred to herein as “aerodynamic diameter”,between about 1 μm and about 5 μm or any subrange encompassed betweenabout 1 μm and about 5 μm. For example, but not limited to, the MMAD isbetween about 1 μm and about 3 μm, or the MMAD is between about 3 μm andabout 5 μm.

Experimentally, aerodynamic diameter can be determined by employing agravitational settling method, whereby the time for an ensemble ofparticles to settle a certain distance is used to infer directly theaerodynamic diameter of the particles. An indirect method for measuringthe mass median aerodynamic diameter (MMAD) is the multi-stage liquidimpinger (MSLI).

The aerodynamic diameter, 4, can be calculated from the equation:

d_(aer)=d_(g)√ρ_(tap)

where d_(g) is the geometric diameter, for example the MMGD, and p isthe powder density.

Particles which have a tap density less than about 0.4 g/cm³, mediandiameters of at least about 1 μm, for eample, at least about 5 μm, andan aerodynamic diameter of between about 1 μm and about 5 μm, preferablybetween about 1 μm and about 3 μm, are more capable of escaping inertialand gravitational deposition in the oropharyngeal region, and aretargeted to the airways, particularly the deep lung. The use of larger,more porous particles is advantageous since they are able to aerosolizemore efficiently than smaller, denser aerosol particles such as thosecurrently used for inhalation therapies.

In comparison to smaller, relatively denser particles the largeraerodynamically light particles, preferably having a median diameter ofat least about 5 μm, also can potentially more successfully avoidphagocytic engulfment by alveolar macrophages and clearance from thelungs, due to size exclusion of the particles from the phagocytes'cytosolic space. Phagocytosis of particles by alveolar macrophagesdiminishes precipitously as particle diameter increases beyond about 3μm. Kawaguchi, H., et al., Biomaterials, 7: 61-66 (1986); Krenis, L. J.and Strauss, B., Proc. Soc. Exp. Med., 107: 748-750 (1961); and Rudt, S.and Muller, R. H., J. Contr. Rel., 22: 263-272 (1992). For particles ofstatistically isotropic shape, such as spheres with rough surfaces, theparticle envelope volume is approximately equivalent to the volume ofcytosolic space required within a macrophage for complete particlephagocytosis.

The particles may be fabricated with the appropriate material, surfaceroughness, diameter and tap density for localized delivery to selectedregions of the respiratory tract such as the deep lung or upper orcentral airways. For example, higher density or larger particles may beused for upper airway delivery, or a mixture of varying sized particlesin a sample, provided with the same or different therapeutic agent maybe administered to target different regions of the lung in oneadministration. Particles having an aerodynamic diameter ranging fromabout 3 to about 5 μm are preferred for delivery to the central andupper airways. Particles having and aerodynamic diameter ranging fromabout 1 to about 3 μm are preferred for delivery to the deep lung.

Inertial impaction and gravitational settling of aerosols arepredominant deposition mechanisms in the airways and acini of the lungsduring normal breathing conditions. Edwards, D. A., J. Aerosol Sci., 26:293-317 (1995). The importance of both deposition mechanisms increasesin proportion to the mass of aerosols and not to particle (or envelope)volume. Since the site of aerosol deposition in the lungs is determinedby the mass of the aerosol (at least for particles of mean aerodynamicdiameter greater than approximately 1 μm), diminishing the tap densityby increasing particle surface irregularities and particle porositypermits the delivery of larger particle envelope volumes into the lungs,all other physical parameters being equal.

The low tap density particles have a small aerodynamic diameter incomparison to the actual envelope sphere diameter. The aerodynamicdiameter, d_(aer), is related to the envelope sphere diameter, d (Gonda,I., “Physico-chemical principles in aerosol delivery,” in Topics inPharmaceutical Sciences 1991 (eds. D. J. A. Crommelin and K. K. Midha),pp. 95-117, Stuttgart: Medpharm Scientific Publishers, 1992)), by theformula:

d_(aer)=d√ρ

where the envelope mass_is in units of g/cm³. Maximal deposition ofmonodispersed aerosol particles in the alveolar region of the human lung(˜60%) occurs for an aerodynamic diameter of approximately d_(aer)=3 μm.Heyder, J. et al., J. Aerosol Sci., 17: 811-825 (1986). Due to theirsmall envelope mass density, the actual diameter d of aerodynamicallylight particles comprising a monodisperse inhaled powder that willexhibit maximum deep-lung deposition is:

d=3/√ρμm (where ρ_(—)<1 g/cm³);

where d is always greater than 3 μm. For example, aerodynamically lightparticles that display an envelope mass density, μ=0.1 g/cm³, willexhibit a maximum deposition for particles having envelope diameters aslarge as 9.5 μm. The increased particle size diminishes interparticleadhesion forces. Visser, J., Powder Technology, 58: 1-10. Thus, largeparticle size increases efficiency of aerosolization to the deep lungfor particles of low envelope mass density, in addition to contributingto lower phagocytic losses.

The aerodynamic diameter can be calculated to provide for maximumdeposition within the lungs. Previously this was achieved by the use ofvery small particles of less than about five microns in diameter,preferably between about one and about three microns, which are thensubject to phagocytosis. Selection of particles which have a largerdiameter, but which are sufficiently light (hence the characterization“aerodynamically light”), results in an equivalent delivery to thelungs, but the larger size particles are not phagocytosed. Improveddelivery can be obtained by using particles with a rough or unevensurface relative to those with a smooth surface.

In another embodiment of the invention, the particles have an envelopemass density, also referred to herein as “mass density” of less thanabout 0.4 g/cm³. Mass density and the relationship between mass density,mean diameter and aerodynamic diameter are discussed in U.S. Pat. No.6,254,854, issued on Jul. 3, 2001, to Edwards, et al., which isincorporated herein by reference in its entirety.

The invention also is related to producing particles that havecompositions and aerodynamic properties described above. The methodincludes spray drying. Generally, spray-drying techniques are described,for example, by K. Masters in “Spray Drying Handbook”, John Wiley &Sons, New York, 1984.

The present invention is related to a method for preparing a dry powdercomposition. In this method, first and second components are prepared,one of which comprises an active agent. For example, the first componentcomprises an active agent dissolved in an aqueous solvent, and thesecond component comprises an excipient dissolved in an organic solvent.The first and second components are combined either directly or througha static mixer to form a combination. The first and second componentsare such that combining them causes degradation in one of thecomponents. For example, the active agent is incompatible with the othercomponent. In such a method, the incompatible active agent is addedlast. The combination is atomized to produce droplets that are dried toform dry particles. In one aspect of this method, the atomizing step isperformed immediately after the components are combined in the staticmixer.

Suitable organic solvents that can be present in the mixture being spraydried include, but are not limited to, alcohols for example, ethanol,methanol, propanol, isopropanol, butanols, and others. Other organicsolvents include, but are not limited to, perfluorocarbons,dichloromethane, chloroform, ether, ethyl acetate, methyl tert-butylether and others. Aqueous solvents that can be present in the feedmixture include water and buffered solutions. Both organic and aqueoussolvents can be present in the spray-drying mixture fed to the spraydryer. In one embodiment, an ethanol/water solvent is preferred with theethanol:water ratio ranging from about 20:80 to about 80:20. The mixturecan have an acidic or alkaline pH. Optionally, a pH buffer can beincluded. Preferably, the pH can range from about 3 to about 10, forexample, from about 6 to about 8.

A method for preparing a dry powder composition is provided. In such amethod, a first phase is prepared that comprises L-Dopa and trehaloseand optionally salts. A second phase is prepared that comprises ethanol.The first and second phases are combined in a static mixer to form acombination. The combination is atomized to produce droplets that aredried to form dry particles. In an Alternative, only the first phase isprepared and atomized to produce droplets that are dried to form dryparticles.

A method for preparing a dry powder composition is provided. In such amethod, a first phase is prepared that comprises L-Dopa and optionallysalts. A second phase is prepared that comprises DPPC in ethanol. Thefirst and second phases are combined in a static mixer to form acombination. The combination is atomized to produce droplets that aredried to form dry particles.

An apparatus for preparing a dry powder composition is provided. Theapparatus includes a static mixer (e.g., a static mixer as more fullydescribed in U.S. Pat. No. 4,511,258, the entirety of which isincorporated herein by reference, or other suitable static mixers suchas, but not limited to, model 1/4-21, made by Koflo Corporation) havingan inlet end and an outlet end. The static mixer is operative to combinean aqueous component with an organic component to form a combination.Means are provided for transporting the aqueous component and theorganic component to the inlet end of the static mixer. An atomizer isin fluid communication with the outlet end of the static mixer toatomize the combination into droplets. The droplets are dried in a dryerto form dry particles. The atomizer can be a rotary atomizer. Such arotary atomizer may be vaneless, or may contain a plurality of vanes.Alternatively, the atomizer can be a two-fluid mixing nozzle. Such atwo-fluid mixing nozzle may be an internal mixing nozzle or an externalmixing nozzle. The means for transporting the aqueous and organiccomponents can be two separate pumps, or a single pump. The aqueous andorganic components are transported to the static mixer at substantiallythe same rate. The apparatus can also include a geometric particle sizerthat determines a geometric diameter of the dry particles, and anaerodynamic particle sizer that determines an aerodynamic diameter ofthe dry particles.

The aqueous solvent and the organic solvent that make up the L-Dopasolution are combined either directly or through a static mixer. TheL-Dopa solution is then transferred to the rotary atomizer (aka spraydryer) at a flow rate of about 5 to 28 g/min (mass) and about 6 to 80ml/min (volumetric). For example, the L-Dopa solution is transferred tothe spray drier at a flow rate of 30 g/min and 31 ml/min. The 2-fluidnozzle disperses the liquid solution into a spray of fine droplets whichcome into contact with a heated drying air or heated drying gas (e.g.,Nitrogen) under the following conditions.

The pressure within the nozzle is from about 10 psi to 100 psi; theheated air or gas has a feed rate of about 80 to 110 kg/hr and anatomization flow rate of about 13 to 67 g/min (mass) and a liquid feedof 10 to 70 ml/min (volumetric); a gas to liquid ratio from about 1:3 to6:1; an inlet temperature from about 90° C. to 150° C.; an outlettemperature from about 40° C. to 71° C.; a baghouse outlet temperaturefrom about 42° C. to 55° C. For example, but not limited to, thepressure within the nozzle is set at 75 psi; the heated gas has a feedrate of 95 kg/hr; and an atomizer gas flow rate of 22.5 g/min and aliquid feed rate of 70 ml/min; the gas to liquid ratio is 1:3; the inlettemperature is 121° C.; the outlet temperature is 48° C.; the baghousetemperature is 43° C.

The contact between the heated nitrogen and the liquid droplets causesthe liquid to evaporate and porous particles to result. The resultinggas-solid stream is fed to the product filter, which retains the finesolid particles and allows that hot gas stream, containing the dryinggas, evaporated water and ethanol, to pass. The formulation and spraydrying parameters are manipulated to obtain particles with desirablephysical and chemical characteristics. Other spray-drying techniques arewell known to those skilled in the art. An example of a suitable spraydryer using rotary atomization includes the Mobile Niro spray dryer,manufactured by Niro, Denmark. The hot gas can be, for example, air,nitrogen, carbon dioxide or argon.

The particles of the invention are obtained by spray drying using aninlet temperature between about 90° C. and about 150° C. and an outlettemperature between about 40° C. and about 70° C.

The particles can be fabricated with a rough surface texture to reduceparticle agglomeration and improve flowability of the powder. Thespray-dried particles have improved aerosolization properties. Thespray-dried particle can be fabricated with features which enhanceaerosolization via dry powder inhaler devices, and lead to lowerdeposition in the mouth, throat and inhaler device.

Methods and apparatus suitable for forming particles of the presentinvention are described in U.S. Patent Application entitled “Method andApparatus for Producing Dry Particles”, filed concurrently herewithunder Attorney Docket No. 00166.0115-US01, which is aContinuation-in-part of U.S. patent application Ser. No. 10/101,563entitled “Method and Apparatus for Producing Dry Particles”, filed onMar. 20, 2002, under the Attorney Docket No. 00166.0115-US00. Methodsand apparatus suitable for forming particles of the present inventionare described in PCT Patent Application entitled “Method and Apparatusfor Producing Dry Particles”, filed concurrently herewith under AttorneyDocket No 00166.0115-WO01. The entire contents of these applications areincorporated by reference herein.

Administration of particles to the respiratory system can be by meanssuch as known in the art. For example, particles are delivered from aninhalation device such as a dry powder inhaler (DPI).Metered-dose-inhalers (MDI), nebulizers or instillation techniques alsocan be employed.

Various suitable devices and methods of inhalation which can be used toadminister particles to a patient's respiratory tract are known in theart. For example, suitable inhalers are described in U.S. Pat. No.4,069,819, issued Aug. 5, 1976 to Valentini, et al., U.S. Pat.No.4,995,385 issued Feb. 26, 1991 to Valentini, et al., and U.S. Pat.No. 5,997,848 issued Dec. 7, 1999 to Patton, et al. Other examplesinclude, but are not limited to, the SPINHALER® (Fisons, Loughborough,U.K.), ROTAHALER® (Glaxo-Wellcome, Research Triangle Technology Park,North Carolina), FLOWCAPS® (Hovione, Loures, Portugal), INHALATOR®(Boehringer-Ingelheim, Germany), and the AEROLIZER® (Novartis,Switzerland), the diskhaler (Glaxo-Wellcome, RTP, NC) and others, suchas known to those skilled in the art. In one embodiment, the inhaleremployed is described in U.S. patent application Ser. No. 09/835,302,entitled “Inhalation Device and Method”, by David A. Edwards, et al.,filed on Apr. 16, 2001 under Attorney Docket No. 00166.0109.US00 and inU.S. patent application Ser. No. 10/268,059, entitled “Inhalation Deviceand Method”, by David A. Edwards, et al., filed on Oct. 10, 2002. Theentire contents of these applications are incorporated by referenceherein.

Delivery to the pulmonary system of particles is by the methodsdescribed in U.S. Patent Application, “High Efficient Delivery of aLarge Therapeutic Mass Aerosol”, application Ser. No. 09/591,307, filedJun. 9, 2000, and U.S. Patent Application, “Highly Efficient Delivery ofA Large Therapeutic Mass Aerosol”, application Ser. No. 09/878,146,filed Jun. 8, 2001. The entire contents of both these applications areincorporated herein by reference. As disclosed therein, particles areheld, contained, stored or enclosed in a receptacle. The receptacle,e.g. capsule or blister, has a volume of at least about 0.37cm³ and canhave a design suitable for use in a dry powder inhaler. Largerreceptacles having a volume of at least about 0.48 cm³, 0.67 cm³ or 0.95cm³ also can be employed.

The methods of the invention also relate to administering to therespiratory tract of a subject, particles and/or compositions comprisingthe particles of the invention, which can be enclosed in a receptacle.As described herein, the invention is drawn to methods of delivering theparticles of the invention, or the invention is drawn to methods ofdelivering respirable compositions comprising the particles of theinvention. As used herein, the term “receptacle” includes but is notlimited to, for example, a capsule, blister, film covered containerwell, chamber and other suitable means of storing particles, a powder ora respirable composition in an inhalation device known to those skilledin the art. Receptacles containing the pharmaceutical composition arestored 2-8° C.

The invention is also drawn to receptacles which are capsules, forexample, capsules designated with a particular capsule size, such as 2,1, 0, 00 or 000. Suitable capsules can be obtained, for example, fromShionogi (Rockville, MD). Blisters can be obtained, for example, fromHueck Foils, (Wall, NJ). Other receptacles and other volumes thereofsuitable for use in the instant invention are known to those skilled inthe art.

In a specific example, dry powder from a dry powder inhaler receptacle,e.g., capsule, holding 25 mg nominal powder dose having at 95% L-Dopaload, i.e., 23.75 mg L-Dopa, could be administered in a single breath.Based on a conservative 4-fold dose advantage, the 23.75 mg delivered inone breath would be the equivalent of about 95 mg of L-Dopa required inoral administration. Several such capsules can be employed to deliverhigher doses of L-Dopa. For instance a size 4 capsule can be used todeliver 50 mg of L-Dopa to the pulmonary system to replace (consideringthe same conservative 4-fold dose advantage) a 200 mg oral dose.

The invention further is related to methods for administering to thepulmonary system a therapeutic dose of the medicament in a small numberof steps, and preferably in a single, breath activated step. Theinvention also is related to methods of delivering a therapeutic dose ofa drug to the pulmonary system, in a small number of breaths, andpreferably in one or two single breaths. The method includesadministering particles from a receptacle having, holding, containing,storing or enclosing a mass of particles, to a subject's respiratorytract.

In one example, at least 80% of the mass of the particles stored in theinhaler receptacle is delivered to a subject's respiratory system in asingle, breath-activated step. In another embodiment, at least 1milligram of L-Dopa is delivered by administering, in a single breath,to a subject's respiratory tract particles enclosed in the receptacle.Preferably at least 10 milligrams of L-Dopa is delivered to a subject'srespiratory tract. Amounts as high as 15, 20, 25, 30, 35, 40 and 50milligrams can be delivered.

Delivery to the pulmonary system of particles in a single,breath-actuated step is enhanced by employing particles which aredispersed at relatively low energies, such as, for example, at energiestypically supplied by a subject's inhalation. Such energies are referredto herein as “low.” As used herein, “low energy administration” refersto administration wherein the energy applied to disperse and/or inhalethe particles is in the range typically supplied by a subject duringinhaling.

The invention also is related to methods for efficiently deliveringpowder particles to the pulmonary system. For example, but not limitedto, at least about 70% or at least about 80% of the nominal powder doseis actually delivered. As used herein, the term “nominal powder dose” isthe total amount of powder held in a receptacle, such as employed in aninhalation device. As used herein, the term nominal drug dose is thetotal amount of medicament contained in the nominal amount of powder.The nominal powder dose is related to the nominal drug dose by the loadpercent of drug in the powder.

Properties of the particles enable delivery to patients with highlycompromised lungs where other particles prove ineffective for thoselacking the capacity to strongly inhale, such as young patients, oldpatients, infirm patients, or patients with asthma or other breathingdifficulties. Further, patients suffering from a combination of ailmentsmay simply lack the ability to sufficiently inhale. Thus, using themethods and particles for the invention, even a weak inhalation issufficient to deliver the desired dose. This is particularly importantwhen using the particles of the instant invention as rescue therapy fora patient suffering from debilitating illness of Parkinson's disease.

Aerosol dosage, formulations and delivery systems may be selected for aparticular therapeutic application, as described, for example, in Gonda,I. “Aerosols for delivery of therapeutic and diagnostic agents to therespiratory tract,” in Critical Reviews in Therapeutic Drug CarrierSystems, 6: 273-313, 1990; and in Moren, “Aerosol dosage forms andformulations,” in: Aerosols in Medicine. Principles, Diagnosis andTherapy, Moren, et al., Eds, Esevier, Amsterdam, 1985.

The method of the invention includes delivering to the pulmonary systeman effective amount of a medicament such as, for example, a medicamentdescribed above. As used herein, the term “effective amount” means theamount needed to achieve the desired effect or efficacy. The actualeffective amounts of drug can vary according to the specific drug orcombination thereof being utilized, the particular compositionformulated, the mode of administration, and the age, weight, conditionof the patient, and severity of the episode being treated. In the caseof a dopamine precursor, agonist or combination thereof it is an amountwhich reduces the Parkinson's symptoms which require therapy. Dosagesfor a particular patient are described herein and can be determined byone of ordinary skill in the art using conventional considerations,(e.g. by means of an appropriate, conventional pharmacologicalprotocol). For example, effective amounts of oral L-Dopa range fromabout 50 milligrams (mg) to about 500 mg. In many instances, a commonongoing (oral) L-Dopa treatment schedule is 100 mg eight (8) times aday.

It has been discovered in this invention that pulmonary delivery ofL-Dopa doses, when normalized for body weight, result in at least a2-fold increase in plasma level as well as in therapeutical advantagesin comparison with oral administration. Significantly higher plasmalevels and therapeutic advantages are possible in comparison with oraladministration. In one example, pulmonary delivery of L-Dopa results ina plasma level increase ranging from about 2-fold to about 10-fold whencompared to oral administration. Plasma levels that approach or aresimilar to those obtained with intravenous administration can beobtained.

Assuming that bioavailability remains the same as dosage is increased,the amount of oral drug, e.g. L-Dopa, required to achieve plasma levelscomparable to those resulting from pulmonary delivery by the methods ofthe invention can be determined at a given point after administration.In a specific example, the plasma levels 2 minutes after oral andadministration by the methods of the invention, respectively, are 1μg/m1L-Dopa and 5 μg/m1L-Dopa. Thus 5 times the oral dose would beneeded to achieve the 5 μg/ml level obtained by administering the drugusing the methods of the invention. In another example, the L-Dopaplasma levels at 120 minutes after administration are twice as high withthe methods of the invention when compared to oral administration. Thustwice as much L-Dopa is required after administration 1 μg/ml followingoral administration in comparison to the amount administered using themethods of the invention.

To obtain a given drug plasma concentration, at a given time afteradministration, less drug is required when the drug is delivered by themethods of the invention than when it is administered orally. Generally,at least a two-fold dose reduction can be employed in the methods of theinvention in comparison to the dose used in conventional oraladministration. A much higher dose reduction is possible. In oneembodiment of the invention, a five fold reduction in dose is employedand reductions as high as about ten fold can be used in comparison tothe oral dose.

At least a two-fold dose reduction also is employed in comparison toother routes of administration, other than intravenous, such as, forexample, intramuscular, subcutaneous, buccal, nasal, intra-peritoneal,and rectal.

In addition or alternatively to the pharmacokinetic effect, (e.g., serumlevel, dose advantage) described above, the dose advantage resultingfrom the pulmonary delivery of a drug, e.g., L-Dopa, used to treatParkinson's disease, also can be described in terms of a pharmacodynamicresponse. Compared to the oral route, the methods of the invention avoidinconsistent medicament uptake by intestines, avoidance of delayeduptake following eating, avoidance of first pass catabolism of the drugin the circulation and rapid delivery from lung to brain via aorticartery.

Preferably, the effective amount is delivered on the “first pass” of theblood to the site of action. The “first pass” is the first time theblood carries the drug to and within the target organ from the point atwhich the drug passes from the lung to the vascular system. Generally,L-Dopa is released in the blood stream and delivered to its site ofaction within a time period which is sufficiently short to providetherapy to the patient being treated. In many cases, L-Dopa can reachthe central nervous system in less than about 10 minutes, often asquickly as two minutes and even faster.

Preferably, the patient's symptoms abate within minutes and generally nolater than one hour. In one embodiment of the invention, the releasekinetics of the medicament are substantially similar to the drug'skinetics achieved via the intravenous route. In another embodiment ofthe invention, the T. of L-Dopa in the blood stream ranges from about 1to about 10 minutes. As used herein, the term T. means the point atwhich levels reach a maximum concentration. In many cases, the onset oftreatment obtained by using the methods of the invention is at least twotimes faster than onset of treatment obtained with oral delivery.Significantly faster treatment onset can be obtained. In one example,treatment onset is from about 2 to about 10 times faster than thatobserved with oral administration.

Particles and methods for delivering L-Dopa to the pulmonary system aredescribed in U.S. patent application Ser. No. 09/665,252 entitled“Pulmonary Delivery In Treating Disorders of the Central NervousSystem”, filed on Sep. 19, 2000, now U.S. Pat. No. 6,514,482 issued onJan. 4, 2003, and U.S. patent application Ser. No. 09/877,734 entitled“Pulmonary Delivery In Treating Disorders of the Central NervousSystem”, filed, Jun. 8, 2001; the contents of both is incorporatedherein by reference in their entirety.

If desired, particles which have fast release kinetics, suitable inrescue therapy, can be combined with particles having sustained release,suitable in treating the chronic aspects of a condition. For example, inthe case of Parkinson's disease, particles designed to provide rescuetherapy can be co-administered with particles having controlled releaseproperties.

The administration of more than one dopamine precursor, agonist orcombination thereof, in particular L-Dopa, carbidopa, apomorphine, andother drugs can be provided, either simultaneously or sequentially intime. Carbidopa, for example, is often administered to ensure thatperipheral carboxylase activity is completely shut down. Intramuscular,subcutaneous, oral and other administration routes can be employed. Inone embodiment, these other agents are delivered to the pulmonarysystem. These compounds or compositions can be administered before,after or at the same time. In a preferred embodiment, particles that areadministered to the respiratory tract include both L-Dopa and carbidopa.The term “co-administration” is used herein to mean that the specificdopamine precursor, agonist or combination thereof and/or othercompositions are administered at times to treat the episodes, as well asthe underlying conditions described herein.

In one embodiment chronic L-Dopa therapy includes pulmonary delivery ofL-Dopa combined with oral carbidopa. In another embodiment, pulmonarydelivery of L-Dopa is provided during the episode, while chronictreatment can employ conventional oral administration ofL-Dopa/carbidopa.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXEMPLIFICATIONS Preparation of Dry Particles Containing L-Dopa Example1 Particles Comprising L-Dopa and Trehalose

Particles with a formulation containing L-Dopa and trehalose wereprepared as follows:

The aqueous solution was formed by adding 2.375 g L-Dopa and 125 mgtrehalose to 700 ml of USP water. The organic solution comprised 300 mlof ethanol. The aqueous solution and the organic solution were combinedin a static mixer. A 1 L total combination volume was used, with a totalsolute concentration of 2.5 g/L in 30/70 ethanol/water. The combinedsolution flowed from the static mixer into a 2 fluid atomizer and theresulting atomized droplets were spray dried under the following processconditions:

-   -   Inlet temperature ˜135° C.    -   Outlet temperature from the drying drum ˜49 to 53° C.    -   Nitrogen drying gas=95 kg/hr    -   Atomization rate=14 g/min    -   2 Fluid internal mixing nozzle atomizer    -   Liquid feed rate=70 ml/min    -   Pressure in drying chamber=−2.0 in water

The resulting particles had a FPF(5.6) of 33%, and a FPF(3.4) of 12%,both measured using a 2-stage ACI.

The combination solution flowing out of the static mixer was fed into arotary atomizer.

The contact between the atomized droplets from the atomizer and theheated nitrogen caused the liquid to evaporate from the droplets,resulting in dry porous particles. The resulting gas-solid stream wasfed to bag filter that retained the resulting dry particles, and allowedthe hot gas stream containing the drying gas (nitrogen), evaporatedwater, and ethanol to pass. The dry particles were collected into aproduct collection vessel.

In order to obtain dry particles of particular physical and chemicalcharacteristics, in vitro characterization tests can be carried out onthe finished dry particles, and the process parameters adjustedaccordingly, as described above. Particles containing 95 wt % L-Dopa and5 wt % trehalose were produced using this method. In this manner, thedesired aerodynamic diameter, geometric diameter, and particle densitycould be obtained for these particles in real-time, during theproduction process.

Example 2 Particles Comprising L-Dopa, Trehalose and Sodium Chloride

Particles with a formulation containing L-Dopa, trehalose and sodiumchloride were prepared as follows: The aqueous solution was formed byadding 2.325 g L-Dopa, 125 mg trehalose and 50 mg sodium chloride to 700ml of USP water. The organic solution comprised 300 ml of ethanol. Theaqueous solution and the organic solution were combined in a staticmixer. A 1 L total combination volume was used, with a total soluteconcentration of 2.5 g/L in 30/70 ethanol/water. The combined solutionflowed from the static mixer into a 2 fluid atomizer and the resultingatomized droplets were spray dried under the following processconditions:

-   -   Inlet temperature ˜135° C.    -   Outlet temperature from the drying drum ˜49 to 53° C.    -   Nitrogen drying gas=95 kg/hr    -   Atomization rate=14 g/min    -   2 Fluid internal mixing nozzle atomizer    -   Liquid feed rate=70 ml/min    -   Liquid feed temperature ˜50° C.    -   Pressure in drying chamber=−2.0 in water

The resulting particles had a FPF(5.6) of 59%, and a FPF(3.4) of 40%,both measured using a 2-stage ACI. The volume mean geometric diameterwas 17 μm at 1.0 bar.

The combination solution flowing out of the static mixer was fed into a2-fluid atomizer. The contact between the atomized droplets from theatomizer and the heated nitrogen caused the liquid to evaporate from thedroplets, resulting in dry porous particles. The resulting gas-solidstream was fed to bag filter that retained the resulting dry particles,and allowed the hot gas stream containing the drying gas (nitrogen),evaporated water, and ethanol to pass. The dry particles were collectedinto a product collection vessel.

In order to obtain dry particles of particular physical and chemicalcharacteristics, in vitro characterization tests can be carried out onthe finished dry particles, and the process parameters adjustedaccordingly, as described above. Particles containing 93 wt % L-Dopa, 5wt % trehalose and 2 wt % sodium chloride produced using this method hada VMGD of 17 μm measured by Rodos at 1 bar and a VMGD of 12 μm at 2 bar,FPF(5.6) of 59%. In this manner, the desired aerodynamic diameter,geometric diameter, and particle density could be obtained for theseparticles in real-time, during the production process.

Example 3 Particles Comprising L-Dopa and DPPC

Particles with a formulation containing L-Dopa and DPPC were prepared asfollows: The aqueous solution was formed by adding 1.1875 g L-Dopa to300 ml of USP water. The organic solution comprised 62.5 mg DPPC in 700ml of ethanol. The aqueous solution and the organic solution werecombined in a static mixer. A 1 L total combination volume was used,with a total solute concentration of 1.25 g/L in 70/30 ethanol/water.The combined solution flowed from the static mixer into a 2 fluidatomizer and the resulting atomized droplets were spray dried under thefollowing process conditions:

-   -   Inlet temperature ˜108° C.    -   Outlet temperature from the drying drum ˜49 to 53° C.    -   Nitrogen drying gas=95 kg/hr    -   Atomization rate=18 g/min    -   2 Fluid internal mixing nozzle atomizer    -   Liquid feed rate=70 ml/min    -   Liquid feed temperature ˜50° C.    -   Pressure in drying chamber=−2.0 in water

The resulting particles had a FPF(5.6) of 29%, and a FPF(3.4) of 10%,both measured using a 2-stage ACI. The volumetric mean geometricdiameter was 7.9 μm at 1 bar.

The combination solution flowing out of the static mixer was fed into arotary atomizer. The contact between the atomized droplets from theatomizer and the heated nitrogen caused the liquid to evaporate from thedroplets, resulting in dry porous particles. The resulting gas-solidstream was fed to bag filter that retained the resulting dry particles,and allowed the hot gas stream containing the drying gas (nitrogen),evaporated water, and ethanol to pass. The dry particles were collectedinto a product collection vessel.

In order to obtain dry particles of particular physical and chemicalcharacteristics, in vitro characterization tests can be carried out onthe finished dry particles, and the process parameters adjustedaccordingly, as described above. Particles containing 95 wt % L-Dopa and5 wt % DPPC were produced using this method. In this manner, the desiredaerodynamic diameter, geometric diameter, and particle density could beobtained for these particles in real-time, during the productionprocess.

Example 4 Particles Comprising L-Dopa, DPPC and Sodium Chloride

Particles with a formulation containing L-Dopa, DPPC and sodium chloridewere prepared as follows: The aqueous solution was formed by adding1.125 g L-Dopa and 25 mg sodium chloride to 300 ml of USP water. Theorganic solution comprised 100 mg DPPC in 700 ml of ethanol. The aqueoussolution and the organic solution were combined in a static mixer. A 1 Ltotal combination volume was used, with a total solute concentration of1.25 g/L in 70/30 ethanol/water. The combined solution flowed from thestatic mixer into a 2 fluid atomizer and the resulting atomized dropletswere spray dried under the following process conditions:

-   -   Inlet temperature ˜108° C.    -   Outlet temperature from the drying drum ˜49 to 53° C.    -   Nitrogen drying gas=95 kg/hr    -   Atomization rate=18 g/min    -   2 Fluid internal mixing nozzle atomizer    -   Liquid feed rate=70 ml/min    -   Liquid feed temperature ˜50° C.    -   Pressure in drying chamber=−2.0 in water

The resulting particles had a FPF(5.6) of 70%, and a FPF(3.4) of 40%,both measured using a 2-stage ACI. The volume mean geometric diameterwas 14 μm at 1.0 bar.

The combination solution flowing out of the static mixer was fed into arotary atomizer. The contact between the atomized droplets from theatomizer and the heated nitrogen caused the liquid to evaporate from thedroplets, resulting in dry porous particles. The resulting gas-solidstream was fed to bag filter that retained the resulting dry particles,and allowed the hot gas stream containing the drying gas (nitrogen),evaporated water, and ethanol to pass. The dry particles were collectedinto a product collection vessel.

In order to obtain dry particles of particular physical and chemicalcharacteristics, in vitro characterization tests can be carried out onthe finished dry particles, and the process parameters adjustedaccordingly, as described above. Particles containing 90 wt % L-Dopa, 8wt % DPPC and 2 wt % sodium chloride produced using this method had aVMGD of 14 μm measured by Rodos at 1 bar and a VMGD of 11 μm at 2 bar,FPF(5.6) of 70%. In this manner, the desired aerodynamic diameter,geometric diameter, and particle density could be obtained for theseparticles in real-time, during the production process.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A composition of dry powder particles formulated for pulmonary delivery comprising about 75 weight percent levodopa or more and sodium chloride.
 2. The composition of claim 1, wherein the particles further comprise a phospholipid or a combination of phospholipids.
 3. The composition of claim 1, wherein the particles have a tap density about 0.4 g/cm³ or less.
 4. The composition of claim 1, wherein the particles have a volume median geometric diameter about 5 micrometers or more.
 5. The composition of claim 1, wherein the particles have an aerodynamic diameter of from about 1 micrometer to about 5 micrometers.
 6. The composition of claim 1, wherein the particles have an aerodynamic diameter of from about 1 micrometer to about 3 micrometers.
 7. The composition of claim 1, wherein the particles have an aerodynamic diameter of from about 3 micrometer to about 5 micrometers.
 8. The composition of claim 1, wherein the particles have a tap density about 0.3 g/cm³ or less.
 9. The composition of claim 1, wherein the particles have a tap density about 0.2 g/cm³ or less.
 10. The composition of claim 1, wherein the particles have a tap density about 0.1 g/cm³ or less.
 11. The composition of claim 1, wherein the particles comprise about 10% or less by weight of sodium chloride.
 12. The composition of claim 1, wherein the particles comprise about 5% or less by weight of sodium chloride.
 13. The composition of claim 1, wherein the particles comprise about 2% or less by weight of sodium chloride.
 14. The composition of claim 2, wherein the phospholipid is dipalmitoyl phosphatidylcholine (DPPC).
 15. A composition of dry powder particles consisting essentially of about 75% or more levodopa, sodium chloride and dipalmitoylphosphatidylcholine.
 16. A composition of dry powder particles consisting essentially of levodopa, sodium chloride and dipalmitoylphosphatidylcholine, wherein the ratio of levodopa:dipalmitoylphosphatidylcholine:sodium chloride is about 90:8:2. 